Shoulder Tenderness Was Associated with the Inflammatory Changes On

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OPEN Shoulder tenderness was associated with the infammatory changes on magnetic resonance imaging in patients with rheumatoid arthritis Satoshi Shinagawa1, Koichi Okamura 1*, Yukio Yonemoto1, Hitoshi Shitara 1, Takahito Suto1, Hideo Sakane1, Trang Thuy Dam2,3, Tsuyoshi Tajika1, Yoshito Tsushima2, Kenji Takagishi1 & Hirotaka Chikuda1

The aim of this study was to assess the association between the shoulder tenderness and the infammatory changes on magnetic resonance imaging (MRI) in the rheumatoid shoulder. Forty-one shoulders of 41 patients with rheumatoid arthritis (RA) were examined. We evaluated synovitis, erosion and bone marrow edema, by counting the numbers of each positive site, and rotator cuf tears on shoulder MRI. The association between the shoulder tenderness and the MRI fndings were statistically analyzed. Twenty-three of 41 patients had tenderness in the shoulder joints. There were 20 shoulders (48.8%) with rotator cuf tear, and no signifcant diference was observed in the prevalence of rotator cuf tear between the tenderness group and non-tenderness group (p = 0.080). There were no signifcant diferences in the demographic data between these two groups. In MRI fndings, we found signifcant diference for the synovitis (p = 0.001) and bone marrow edema (p = 0.021). Synovitis was strongly associated with the shoulder tenderness (OR: 3.996, 95% CI: 1.651–9.671). Synovitis was the factor most associated with shoulder tenderness.

Rheumatoid arthritis (RA) is a chronic infammatory disease characterized by synovial infammation and bone and cartilage destruction which leads to severe disability and premature mortality. RA afects the large joints more than the peripheral joints in the later stages of the disease1–3. Among those large joints, 50% of RA patients have tenderness in their shoulder joints and 30% of them have decreased shoulder function one year following RA onset4. Te destruction of shoulder joint leads to functional disabilities in their daily and work life and a decrease in the patients’ quality of life5,6. Te shoulder joint is a complex joint which is difcult to confrm accurately the joint swelling by physical examination. Terefore, the shoulder lesions are ofen underdiagnosed4. Structural joint damage of RA has been traditionally assessed by conventional radiography (CR) which is based on the presence of bone erosions, joint space narrowing and osteoporosis7. It is possible that CR images are not able to detect actual erosions of the shoulder joints in RA patients because of two-dimensional imaging. Conversely, the examination with magnetic resonance imaging (MRI) to the shoulder joints was reported to be useful. It can not only detect rotator cuf changes but also synovitis and erosions, much earlier with a higher sensitivity. MRI can also identify bone marrow edema, which is thought to be one of the predictive factors for joint destructions8–11. Te shoulder joint is a complex joint which is difcult to confrm accurately the joint efusion by physical examination because of its deep location. Tis leads the shoulder lesions to be ofen underdiagnosed11. Tere have been several reports evaluating the clinical status of RA using imaging modalities, such as CR12, ultrasound (US)13,14, MRI15,16 and FDG-PET17–19. However, few reports demonstrated the association between the tenderness of shoulder and each imaging20.

1Department of Orthopaedic Surgery, Graduate School of Medicine, Gunma University, Gunma, Japan. 2Department of Diagnostic Radiology and Nuclear Medicine, Graduate School of Medicine, Gunma University, Gunma, Japan. 3Department of Radiology, Hanoi Medical University, Hanoi, Vietnam. *email: [email protected]

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Terefore, in this study, we investigated the associations between the shoulder tenderness and the MRI fndings in patients with RA. Materials and Methods Patients. Te Institutional Review Board of Gunma University Hospital, which complies with the principles of the Declaration of Helsinki, approved the protocol for this study. Te informed consent was obtained from each patient and all methods were performed in accordance with the relevant guidelines and regulations. Te consecutive 58 patients with RA were recruited to this study, who fulflled the American College of Rheumatology 1987 revised criteria for RA21 and need to receive the anti-cytokine therapies from 2008 to 2010 in our hospital. Seventeen patients were excluded: ten declined to participate, fve with renal dysfunction, and one with rheumatoid vasculitis. Tus, we investigated 41 shoulders from 41 patients. Two certifed rheumatologists checked the tenderness of glenohumeral joint and recognized as the shoulder tenderness when the patients declare the tenderness. Te shoulder CR and MRI images were examined on the same day. Te examinations for 23 patients with tenderness were performed on the afected side, while analyses for the 18 patients without tenderness on both shoulders were performed randomly on either side. An anteroposterior radiograph of the shoulder was obtained from each patient. Te joint damage was assessed by a certifed rheumatologist (Y.Y) (who had no prior knowledge of the clinical fndings and results of the other imaging techniques) using the Larsen grade (0-V)7. For clinical evaluation, the patients were assessed using the Steinbrocker classifcation system22, the positive rates of rheumatoid factor (RF), anti-cyclic citrullinated peptide antibody (ACPA), the levels of the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), matrix metalloproteinase-3 (MMP-3), and the disease activity score (DAS) 28-ESR and DAS28-CRP23.

Magnetic resonance imaging (MRI). MRI was performed on a 1.5 T MR unit (Signa HDx, General Electric Healthcare, Milwaukee, WI, USA) using a three-channel phased array coil with the patient placed in the supine position and the adducted arm in neutral position. Te following imaging sequences were used: T1, T1-weighted fast spin-echo imaging (repetition time (TR) of 465 mseconds, echo time (TE) of 10.1 mseconds, slice thickness (SL) of 4 mm, matrix size of 224 × 384 pixels, and feld of view (FOV) of 180 mm) in the oblique coronal plane which was parallel to the course of the tendon of supraspinatus muscle; T2 FS, T2-weighted fast spin-echo sequences with frequency-selective fat saturation (TR of 4000 mseconds, TE of 102 mseconds, SL of 4 mm, matrix size of 224 × 384 pixels, and FOV of 180 mm) in the oblique coronal plane; Gd-DTPA T1 FS, T1-weighted fast spin-echo sequences with frequency-selective fat saturation (TR of 465 mseconds, TE of 10.1 mseconds, SL of 4 mm, matrix size of 192 × 384 pixels, and FOV of 180 mm) afer intravenous administration of gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA, Magnevist, Bayer Yakuhin, Ltd., Osaka, Japan, 0.1 mmol/kg of body weight) in the axial and oblique coronal planes. Te evaluations of MRI images, such as synovitis, erosion and bone marrow edema, were defned according to previous studies24,25, as below. Te images were evaluated using the following methods by two specialists for the shoulder joints, who are familiar with the images of shoulder joints and were blinded to the clinical status and CR fndings. Synovitis was defined as thickened synovium (>2 mm) enhanced on Gd-DTPA T1 FS. The number of synovitis-positive sites among the sub-acromial bursa (SAB), sub-deltoid bursa (SDB), axillary pouch (AP), rotator interval (RI) and biceps pulley (BP) were counted (Fig. 1a–c). Erosion was defned as a defect >2 mm of the cortical bone which showed low signal intensity on T1 and enhanced on Gd-DTPA T1 FS. Te number of erosion-positive sites among the supraspinatus (SSP) insertion site, infraspinatus (ISP) insertion site, subscapularis (SSC) insertion site, joint surface of the humeral head and glenoid fossa were counted (Fig. 1d,e). Bone marrow edema was defned as a lesion that showed a high signal intensity on T2 FS and a low signal intensity on T1-weighted images and enhanced on Gd-DTPA T1 FS within the trabecular bone. Te number of bone edema-positive sites among the SSP insertion site, ISP insertion site, SSC insertion site and subchondral bone of the humeral head were counted (Fig. 1f,g). The existence of rotator cuff tear of SSP-ISP was also assessed using oblique coronal T2 FS (Fig. 1h). Full-thickness and partial-thickness tears were considered as rotator cuf tear as previously described by Reinus26 and Teefey27.

Statistical analysis. Te Spearman’s rank correlation test was applied to evaluate the correlations between the Larsen grades and the existence of rotator cuf tear. Te Mann–Whitney U test, the chi-square test, and Fisher’s exact test were used for comparisons between with and without tenderness groups. In addition, a logistic analysis was performed to elucidate factors associated with shoulder tenderness. IBM SPSS Statistics 25 sofware program (IBM Corp., Armonk, NY, USA) was used for all statistical analyses. A value of p < 0.05 was considered to be statistically signifcant. Results Te clinical characteristics are shown in Table 1. Twenty shoulders (48.8%) had rotator cuf tear (14 shoulders were in tenderness group, and 6 shoulders in the non-tenderness group). Te prevalence of rotator cuf tear with each Larsen grade is shown in Fig. 2. Tere was a positive correlation between the existence of rotator cuf tear and Larsen grade (r = 0.614, p < 0.001). Te clinical characteristics and MRI fndings were compared between patients with and without shoulder tenderness (Table 2). Tere were no signifcant diferences in demographic data between those two groups. Te number of positive sites based on the MRI fndings in the groups with/without shoulder tenderness were as

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Figure 1. Te infammatory changes on MRI. Te shoulder images are Gd-DTPA T1 FS sequences showing the synovitis (a–c), the erosion (d,e), the bone edema (f,g), and oblique coronal T2 FS showing the rotator cuf tear (h). Gd-DTPA: gadolinium-diethylenetriamine pentaacetic acid, T1 FS: T1-weighted fast spin-echo sequences with frequency-selective fat saturation, T2 FS: T2-weighted fast spin-echo sequences with frequency-selective fat saturation, SAB: sub-acromial bursa, SDB: sub-deltoid bursa, AP: axillary pouch, RI: rotator interval, BP: biceps pulley, SSP: supraspinatus, ISP: infraspinatus, SSC: subscapularis.

follows: synovitis; 3.0 ± 1.4/0.7 ± 1.0, erosion; 3.0 ± 1.6/2.3 ± 1.3 bone marrow edema; 1.9 ± 1.3/1.2 ± 1.4. Tere were signifcant diferences between the two groups for synovitis positive sites (p < 0.001) and bone marrow edema positive sites (p = 0.021).

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Characteristic Mean ± SD (range) Sex (male/female) 8/33 Age (years) 53.3 ± 15.5 (17–72) Disease duration (years) 11.9 ± 12.3 (0–53) Larsen grade (0/I/II/III/IV/V) 4/15/7/2/5/8 Steinbrocker stage (I/II/III/IV) 6/13/8/14 Steinbrocker class (1/2/3/4) 9/18/14/0 MTX: usage/dose (mg/week) 82.9%/6.9 ± 1.6 (4.0–10.0) PSL: usage/dose (mg/day) 63.4%/4.1 ± 2.1 (1.0–10.0) RF positivity 68% ACPA positivity 79% ESR (mm/h) 60.0 ± 30.8 CRP (mg/dl) 2.3 ± 2.5 MMP-3 (ng/ml) 273.2 ± 275.5 DAS28-ESR 5.4 ± 1.2 DAS28-CRP 4.5 ± 1.1

Table 1. Te clinical characteristics of the patients. MTX: methotrexate, PSL: prednisolone, RF: rheumatoid factor, ACPA: anti-cyclic citrullinated peptide antibody, ESR: erythrocyte sedimentation rate, CRP: C-reactive protein, MMP-3: matrix metalloproteinase-3, DAS: disease activity score.

Figure 2. Te presence and absence of rotator cuf tears for each Larsen grade. RCT: rotator cuf tear. Te number of RCT is as follows: Larsen grade 0: 0/4 (0%), grade I: 4/15 (26.7%), grade II: 4/8 (50.0%), grade III: 2/2 (100%), grade IV: 3/5 (60.0%), grade V: 8/8 (100%).

Te existence of shoulder tenderness was taken as a dependent variable and the numbers of sites detected as synovitis, erosion, bone marrow edema, and rotator cuf tear were used as explanatory variables in the logistic regression analysis. Te most strongly associated factor with shoulder tenderness was synovitis detected with MRI (OR: 3.996, 95% CI: 1.651–9.671) (Table 3). In the non-tenderness group, 27.8% and 22.2% had synovitis at SAB and RI. On the other hand, in the tenderness group, 82.6% had synovitis at SAB, 52.2% at SDB, 65.2% at AP and RI. Te incidences of all sites about synovitis in the tenderness group were higher than in the non-tenderness group. Signifcant diferences between two groups for synovitis positive sites at SAB, SDB, AP and RI were seen (p = 0.001, p = 0.001, p = 0.001, p = 0.007, respectively) (Table 4). Te intra-rater reliability for synovitis, erosion and bone marrow edema were 0.977, 0.877, and 0.879 and inter–rater reliability for those were 0.939, 0.902, and 0.918. Discussion In this study, we qualitatively evaluated the shoulder joints with RA patients using MRI and investigated the association between shoulder tenderness and MRI fndings. We counted the number of infammation sites on shoulder MRI which were positive for synovitis, erosion and bone marrow edema in reference to the OMERACT-RAMRIS scoring system24 and the Nagasaki score28,29. Ten, we investigated these infammatory

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Shoulders with Shoulders without tenderness n = 23 tenderness n = 18 p-value Background Sex (male/female) 6/17 2/16 0.213 Age (years) 54.6 ± 16.0 (17–72) 52.6 ± 15.6 (18–71) 0.762 Disease duration (years) 14.0 ± 14.2 (0.6–53.0) 8.6 ± 8.6 (0.6–30.0) 0.378 Steinbrocker stage (I/II/III/IV) 2/7/3/11 4/6/5/3 0.152 Steinbrocker class (1/2/3/4) 3/11/9/0 6/7/5/0 0.293 Larsen grade (0/I/II/III/IV/V) 1/8/2/2/4/6 3/7/5/0/1/2 0.176 use of MTX 83.3% 83.3% 1.00 dose of MTX (mg/week) 6.7 ± 1.6 (4.0–10.0) 7.3 ± 1.6 (4.0–10.0) 0.285 use of PSL 62.5% 66.7% 0.780 dose of PSL (mg/day) 4.6 ± 2.4 (1.0–10.0) 3.6 ± 1.5 (1.0–5.0) 0.317 ESR (mm/h) 59.1 ± 34.0 63.7 ± 28.4 0.430 CRP (mg/dl) 2.6 ± 2.8 2.3 ± 2.6 0.948 MMP-3 (ng/ml) 232.4 ± 220.6 330.8 ± 336.0 0.193 RF positivity 65.2% 66.7% 0.923 ACPA positivity 81.8% 76.5% 0.682 DAS28-ESR 5.6 ± 1.3 5.2 ± 1.0 0.291 DAS28-CRP 4.8 ± 1.2 4.3 ± 1.0 0.121 MRI fndings Rotator cuf tear 62.5% 33.3% 0.080 Synovitis 3.0 ± 1.4 0.7 ± 1.0 <0.001* (0/1/2/3/4/5) (2/1/5/7/5/3) (10/4/3/1/0/0) Erosion 3.0 ± 1.6 2.3 ± 1.3 0.101 (0/1/2/3/4/5) (2/1/7/3/4/6) (1/4/6/4/2/1) Bone edema 1.9 ± 1.3 1.2 ± 1.4 0.021* (0/1/2/3/4) (5/3/6/6/3) (10/3/2/2/1)

Table 2. Te diferences in the background factors and MRI fndings in the patients with and without shoulder tenderness. MTX: methotrexate, PSL: prednisolone, RF: rheumatoid factor, ACPA: anti-cyclic citrullinated peptide antibody, ESR: erythrocyte sedimentation rate, CRP: C-reactive protein, MMP-3: matrix metalloproteinase-3, DAS: disease activity score, MRI: magnetic resonance imaging. Te Mann–Whitney U test, the chi-square test, and Fisher’s exact test were used for comparisons between the two groups. *Indicates a signifcant diference (p < 0.05).

Odds ratio 95% CI p-value Synovitis 3.996 1.651–9.671 0.002* Rotator cuf tear 1.938 0.135–27.790 0.626 Bone marrow 1.316 0.576–3.010 0.515 edema Erosion 0.677 0.281–1.636 0.386

Table 3. Te association between the infammatory changes and shoulder tenderness. CI: confdence interval, *indicates a signifcant diference according to the logistic regression analysis (p < 0.05).

changes by MRI and examined their associations with shoulder tenderness. Our results indicated that synovitis would highly associate with shoulder tenderness in RA. Synovitis and erosions can be detected more readily by MRI than CR, and bone marrow edema can only be defned by MRI30, MRI is useful in locating RA lesions which are undetectable by CR and considered to lead to the future joint destructions31–34. In our study, on the even early stage of Larsen grades, some patients had high synovitis and bone marrow edema scores on MRI, independently of severity of RA. Te regression analysis revealed that the most strongly associated factor with shoulder tenderness was synovitis detected by MRI. In US study, Hirata et al.20 reported that lower concordance of shoulder tenderness and US-detected synovitis in RA. Te diference between these two modalities are the possible sites for the detection of synovitis. When evaluated with MRI, the multiple detections of shoulder synovitis are more capable than the US, and this might lead to the high concordance in the MRI. In the clinical situation, synovitis should be treated intensively to prevent the future damage of the joints. Terefore, it might be suggested that the physician should consider examining the shoulder joints with MRI to check whether there is synovitis if the patients have long-lasting tenderness at shoulder joints.

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tenderness group non-tenderness group n = 23 n = 18 p value SAB (%) 82,6 27.8 0.001* SDB (%) 52.2 5.6 0.001* Synovitis positive AP (%) 65.2 11.1 0.001* RI (%) 65.2 22.2 0.007* BP (%) 26.1 5.6 0.112

Table 4. Te location of synovitis on MRI. SAB: sub-acromial bursa, SDB: sub-deltoid bursa, AP: axillary pouch, RI: rotator interval, BP: biceps pulley. *Indicates a signifcant diference according to Fisher’s exact test (p < 0.05).

Te additional benefts of utilizing MRI in RA patients are the screening and detection of sof tissue damages, such as rotator cuf tears. Te causes of rotator cuf tears in RA patients are not only increased age and traumatic injuries but chronic infammation near the attachments of rotator cufs. Neer et al.35 found 42.0% (29/69) of rheumatoid shoulders had a complete tear of rotator cuff at total shoulder arthroplasty. Te patients in their study could not use the methotrexate (MTX) and other biological disease-modifying anti-rheumatic drugs (DMARDs) since it was possible afer their study that the MTX and the biological DMARDs could be administered to RA patients. In our study, although the MTX was administered to over 80% of the patients, 48.8% of our population had rotator cuf tears. Tese might be explained by the high disease activity of the patients in our study since they were just before the treatment of biological DMARDs. Additionally, these two rates are higher than the general population (20.7%)36. Regarding the rotator cuf tears and Larsen grades, some previous studies have demonstrated that rotator cuf was the more thinning and torn in the more advanced stage of the Larsen grades37–39. Conversely, other reports have reported that there was no signifcant association between the Larsen grade and the rate of rotator cuf tears40. Our result was in agreement with the latter. Further research should be planned to reveal the overview of the rotator cuf tears in patients with RA, especially in the era of MTX and biological DMARDs. Tere are some limitations to this study. First, this study was a retrospective cross-sectional study. Second, the patient group in this study tended to have high disease activity since they needed to receive biological therapies. Tird, this study is cross sectional study and there was no information about the disappearance of the tenderness along with the treatment. Further longitudinal study is needed. Te destruction of the shoulder joint in RA patients occurred gradually, and resulting in decreased function41. To avoid the joint destruction, early detection of infammation in the shoulder joints is necessary. From this study, when the shoulder tenderness is found, the imaging examination to evaluate synovitis in that joint should be considered. Conclusion We evaluated synovitis, erosion, bone marrow edema and rotator cuf tear on shoulder MRI in RA patients and analyzed the association of these fndings with the shoulder tenderness. Synovitis was the factor most associated with shoulder tenderness. Data availability Data sharing is not applicable to this article.

Received: 24 April 2019; Accepted: 2 December 2019; Published: xx xx xxxx References 1. Pincus, T. et al. Severe functional declines, work disability, and increased mortality in seventy-fve rheumatoid arthritis patients studied over nine years. Arthritis Rheum. 27, 864–872 (1984). 2. Scott, D. L., Symmons, D. P., Coulton, B. L. & Popert, A. J. Long-term outcome of treating rheumatoid arthritis: results afer 20 years. Lancet 1, 1108–1111 (1987). 3. Gardner, D. L. Rheumatoid arthritis: cell and tissue pathology in Pathological basis of connective tissue disease (ed. Gardner, D. L.) 444–526 (Edward,Arnold, 1992). 4. Olofsson, Y., Book, C. & Jacobsson, L. Shoulder joint involvement in patients with newly diagnosed rheumatoid arthritis. Prevalence and associations. Scandinavian Journal of Rheumatology 32, 25–32, https://doi.org/10.1080/03009740310000364 (2003). 5. Goldhahn, J., Kolling, C., Gay, S. & Simmen, B. R. Functional staging and surgical intervention of the elbow and shoulder joints in a patient with rheumatoid arthritis. Nat Clin Pract Rheumatol 3, 112–117 (2007). 6. Petersson, C. J. Painful shoulders in patients with rheumatoid arthritis. Prevalence, clinical and radiological features. Scand J Rheumatol. 15, 275–279 (1986). 7. Larsen, A., Dale, K. & Eek, M. Radiographic evaluation of rheumatoid arthritis and related conditions by standard reference flms. Acta Radiol Diagn (Stockh). 18, 481–491 (1977). 8. Sperling, J. W., Cofeld, R. H., Schleck, C. D. & Harmsen, W. S. Total shoulder arthroplasty versus hemiarthroplasty for rheumatoid arthritis of the shoulder: results of 303 consecutive cases. J Shoulder Elbow Surg. 16, 683–690 (2007). 9. McQueen, F. M. Bone marrow edema and osteitis in rheumatoid arthritis: the imaging perspective. Arthritis Res Ter. 14, 224 (2012). 10. Amin, M. F., Ismail, F. M. & El Shereef, R. R. Te role of ultrasonography in early detection and monitoring of shoulder erosions, and disease activity in rheumatoid arthritis patients; comparison with MRI examination. Acad Radiol. 19, 693–700 (2012). 11. Tomas, T. et al. Te rheumatoid shoulder: current consensus on diagnosis and treatment. Joint Bone Spine 73, 139–143 (2006).

Scientific Reports | (2019)9:19599 | https://doi.org/10.1038/s41598-019-55938-6 6 www.nature.com/scientificreports/ www.nature.com/scientificreports

12. Kaneko, A. et al. Development and validation of a new radiographic scoring system to evaluate bone and cartilage destruction and healing of large joints with rheumatoid arthritis: ARASHI (Assessment of rheumatoid arthritis by scoring of large joint destruction and healing in radiographic imaging) study. Mod Rheumatol. 23, 1053–1062 (2013). 13. Kawashiri, S. Y. et al. Te power Doppler ultrasonography score from 24 synovial sites or 6 simplifed synovial sites, including the metacarpophalangeal joints, refects the clinical disease activity and level of serum biomarkers in patients with rheumatoid arthritis. Rheumatology (Oxford) 50, 962–965 (2011). 14. Bruyn, G. A. et al. Validity of ultrasonography and measures of adult shoulder function and reliability of ultrasonography in detecting shoulder synovitis in patients with rheumatoid arthritis using magnetic resonance imaging as a gold standard. Arthritis Care Res (Hoboken). 62, 1079–1086 (2010). 15. McQueen, F. M. et al. Magnetic resonance imaging of the wrist in early rheumatoid arthritis reveals a high prevalence of erosions at four months afer symptom onset. Ann Rheum Dis. 57, 350–356 (1998). 16. Murakami, D. M., Bassett, L. W. & Seeger, L. L. Advances in imaging of rheumatoid arthritis. Clin Orthop Relat Res. 265, 83–95 (1991). 17. Okamura, K. et al. Te assessment of biologic treatment in patients with rheumatoid arthritis using FDG-PET/CT. Rheumatology (Oxford) 51, 1484–1491 (2012). 18. Okamura, K. et al. Evaluation of tocilizumab therapy in patients with rheumatoid arthritis based on FDG-PET/CT. BMC Musculoskelet Disord. 15, 393, https://doi.org/10.1186/1471-2474-15-393 (2014). 19. Yonemoto, Y. et al. [(18)F]fuorodeoxyglucose uptake as a predictor of large joint destruction in patients with rheumatoid arthritis. Rheumatol Int. 36, 109, https://doi.org/10.1007/s00296-015-3331-0 (2016). 20. Hirata, A. et al. Concordance of Patient-Reported Joint Symptoms, Physician-Examined Arthritic Signs, and Ultrasound-Detected Synovitis in Rheumatoid Arthritis. Arthritis Care Res (Hoboken). 69, 801–806 (2017). 21. Arnett, F. C. et al. Te American Rheumatism Association 1987 revised criteria for the classifcation of rheumatoid arthritis. Arthritis Rheum. 31, 315–324 (1988). 22. Steinbrocker, O., Traeger, C. H. & Batterman, R. C. Terapeutic criteria in rheumatoid arthritis. JAMA. 140, 659–662 (1949). 23. Te DAS-score website. http://www.das-score.nl/. 24. Østergaard, M. et al. The OMERACT Rheumatoid Arthritis Magnetic Resonance Imaging (MRI) Scoring System: Updated Recommendations by the OMERACT MRI in Arthritis Working Group. J Rheumatol. 44, 1706–1712 (2017). 25. Yonemoto, Y. et al. Predictive factors related to shoulder joint destruction in rheumatoid arthritis patients treated with biologics: A prospective study. Mod Rheumatol. 27, 587–592 (2017). 26. Reinus, W. R., Shady, K. L., Mirowitz, S. A. & Totty, W. G. MR diagnosis of rotator cuf tears of the shoulder: value of using T2- weighted fat-saturated images. Am J Roentgenol. 164, 1451–1455 (1995). 27. Teefey, S. A. et al. Detection and quantifcation of rotator cuf tears. Comparison of ultrasonographic, magnetic resonance imaging, and arthroscopic fndings in seventy-one consecutive cases. J Bone Joint Surg Am. 86, 708–716 (2004). 28. Tamai, M. et al. Early prediction of rheumatoid arthritis by serological variables and magnetic resonance imaging of the wrists and fnger joints: results from prospective clinical examination. Ann Rheum Dis. 65, 134–135 (2006). 29. Tamai, M. et al. A prediction rule for disease outcome in patients with undiferentiated arthritis using magnetic resonance imaging of the wrists and fnger joints and serologic autoantibodies. Arthritis Rheum. 61, 772–778 (2009). 30. Alasaarela, E. et al. Evaluation of humeral head erosions in rheumatoid arthritis: a comparison of ultrasonography, magnetic resonance imaging, computed tomography and plain radiography. Br J Rheumatol. 37, 1152–1156 (1998). 31. Hetland, M. L. et al. CIMESTRA study group: Radiographic progression and remission rates in early rheumatoid arthritis - MRI bone oedema and anti-CCP predicted radiographic progression in the 5-year extension of the double-blind randomised CIMESTRA trial. Ann Rheum Dis. 69, 1789–1795 (2010). 32. Haavardsholm, E. A., Bøyesen, P., Østergaard, M., Schildvold, A. & Kvien, T. K. Magnetic resonance imaging fndings in 84 patients with early rheumatoid arthritis: bone marrow oedema predicts erosive progression. Ann Rheum Dis. 67, 794–800 (2008). 33. Bøyesen, P. et al. MRI in early rheumatoid arthritis: synovitis and bone marrow oedema are independent predictors of subsequent radiographic progression. Ann Rheum Dis. 70, 428–433 (2011). 34. Hetland, M. L. et al. CIMESTRA study group: MRI bone oedema is the strongest predictor of subsequent radiographic progression in early rheumatoid arthritis. Results from a 2-year randomised controlled trial (CIMESTRA). Ann Rheum Dis. 68, 384–390 (2009). 35. Neer, C. S. 2nd, Watson, K. C. & Stanton, F. J. Recent experience in total shoulder replacement. J Bone Joint Surg Am. 64, 319–337 (1982). 36. Yamamoto, A. et al. Prevalence and risk factors of a rotator cuf tear in the general population. J Shoulder Elbow Surg. 19, 116–120 (2010). 37. Lehtinen, J. T. et al. Subacromial space in the rheumatoid shoulder: a radiographic 15-year follow-up study of 148 shoulders. J Shoulder Elbow Surg. 9, 183–187 (2000). 38. Weiss, J. J., Tompson, G. R., Doust, V. & Burgener, F. Rotator cuf tears in rheumatoid arthritis. Arch Intern Med. 135, 521–525 (1975). 39. Soini, I., Belt, E. A., Niemitukia, L., Mäenpää, H. M. & Kautiainen, H. J. Magnetic resonance imaging of the rotator cuf in destroyed rheumatoid shoulder: comparison with fndings during shoulder replacement. Acta Radiol. 45, 434–439 (2004). 40. Kavanaugh, A., Eshaghi, N., Cush, J. & Awad, R. Rotator cuf dysfunction in patients with rheumatoid arthritis. J Clin Rheumatol. 1, 274–279 (1995). 41. van der Zwaal, P. et al. Te natural history of the rheumatoid shoulder: a prospective long-term follow-up study. Bone Joint J. 96, 1520–1524 (2014).

Acknowledgements We thank Koichi Ujita, a medical radiographer at the Department of Radiology, Gunma University Hospital, for advising and performing the MRI imaging. Author contributions S.S. and K.O. wrote the main manuscript text and revised the manuscript; S.S., K.O., Y.Y., Y.T., K.T. and H.C. designed the study, S.S., Y.Y., T.S., H.S., D.T.T. and T.T. collected the data. H.S. analyzed the data. All authors reviewed the manuscript. Competing interests Te authors declare no competing interests. Additional information Correspondence and requests for materials should be addressed to K.O.

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Scientific Reports | (2019)9:19599 | https://doi.org/10.1038/s41598-019-55938-6 8